bHLH Transcription Factors in Neural Development

神经发育中的 bHLH 转录因子

• 批准号: 8644810
• 负责人: Jane E Johnson
• 金额: $ 32.84万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644810
• 关键词: Autistic Disorder; Binding; Biochemical; Biological Assay; Boxing; Brain Diseases; Brain Stem; Cells; Cerebellum; Characteristics; Complex; Coupling; Developmental Process; Dorsal; Down-Regulation; Elements; Enhancers; Epilepsy; Equilibrium; Family; Family member; Gene Expression Regulation; Genes; Genetic Enhancer Element; Genetic Transcription; Glutamates; Goals; Homeostasis; Hyperalgesia; In Vitro; Interneurons; Link; Mediating; Molecular; Mutation; Nervous system structure; Neural tube; Neuraxis; Neuronal Differentiation; Neurons; Pathway interactions; Phenotype; Posterior Horn Cells; Reading; Regulation; Reporter; Retina; Role; Signal Pathway; Signal Transduction; Site; Specific qualifier value; Specificity; Spinal Cord; Stem cells; System; Testing; Therapeutic; Time; Transcription Initiation; Transcription Repressor/Corepressor; Transcriptional Regulation; Zinc Fingers; cell type; diencephalon; dorsal horn; excitatory neuron; genome-wide; histone methyltransferase; in vivo; inhibitory neuron; insight; loss of function; mutant; nerve stem cell; nervous system disorder; neurodevelopment; neuronal circuitry; progenitor; programs; public health relevance; regenerative; somatosensory; stem; stem cell fate; success; transcription factor

DESCRIPTION (provided by applicant): An increasing number of diseases of the brain are being linked to deviations from the normally carefully calibrated balance between excitatory and inhibitory neuronal activities. A critical choice point for establishing this inhibitory/excitatory neuronal balance is governed by the transcription factor Ptf1a. Ptf1a is a bHLH transcription factor that is required for GABAergic inhibitory neurons in the dorsal spinal cord, cerebellum, and retina. In the absence of Ptf1a, neural progenitor cells fail to generate inhibitory neurons and aberrantly assume an excitatory neuronal phenotype. Uncovering the transcriptional control of Ptf1a expression and the function of its downstream targets will provide molecular insight into developmental processes regulating the neuronal circuitry in multiple regions of the central nervous system. Because of the timing and the mechanism of PTf1a function, it provides a unique opportunity to uncover the molecular mechanisms that couple neuronal differentiation and neuronal subtype specification. Identification of cis-regulatory sequences in the Ptf1a gene locus revealed separable elements controlling transcription initiation, autoregulation, restriction to dI4/dIL progenitors, and downregulation as the cells differentiate to inhibitory neurons. In addition, direct targets of Ptf1a have been identified that serve as candidates for mediating inhibitory neuronal identity while suppressing excitatory neuron identity. The goal of the current project is to build on these findings to 1) identify trans-acting upstream factors and signaling pathways that function through the cis-regulatory sequences to regulate Ptf1a, and 2) determine the function of a downstream target of Ptf1a in specification of interneurons in the dorsal horn, cerebellum, and retina. Success in this program will impact understanding of how stem/progenitor cells transition to mature cell types and generate the neuronal diversity required for circuit formation. Identifying the pathways that direct cells down a specific lineage may have therapeutic value in stem cell manipulation and treatment of neurological disorders.

描述（由申请人提供）：越来越多的脑疾病与兴奋性和抑制性神经元活动之间正常仔细校准的平衡偏离有关。建立这种抑制性/兴奋性神经元平衡的关键选择点由转录因子Ptf 1a控制。Ptf 1a是背侧脊髓、小脑和视网膜中GABA能抑制性神经元所需的bHLH转录因子。在没有Ptf 1a的情况下，神经祖细胞不能产生抑制性神经元，并且异常地呈现兴奋性神经元表型。揭示Ptf 1a表达的转录控制及其下游靶点的功能将为调节中枢神经系统多个区域神经元回路的发育过程提供分子见解。由于PTf 1a功能的时间和机制，它提供了一个独特的机会，揭示耦合神经元分化和神经元亚型规范的分子机制。Ptf 1a基因位点的顺式调控序列的鉴定揭示了控制转录起始、自身调节、对dI 4/dIL祖细胞的限制以及随着细胞分化为抑制性神经元而下调的可分离元件。此外，Ptf 1a的直接靶点已被确定为介导抑制性神经元身份同时抑制兴奋性神经元身份的候选者。目前项目的目标是建立在这些发现的基础上，1）确定反式作用的上游因子和信号通路，通过顺式调节序列调节Ptf 1a，2）确定Ptf 1a下游靶点在背角，小脑和视网膜中的中间神经元的功能。该计划的成功将影响对干/祖细胞如何转变为成熟细胞类型并产生回路形成所需的神经元多样性的理解。识别引导细胞沿着特定谱系的途径可能在干细胞操作和神经系统疾病的治疗中具有治疗价值。